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      Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

      research-article
      1 , , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 4 , 2 , 3 , 2 , 3 , 2 , 3 , 1 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 4 , 2 , 5 , 4 , 1 , 6 , 1 , 2 , 3 , 2 , 3 , 2 , 3 , Oxford COVID Vaccine Trial Genetics Study Team Group, 2 , 3 , 2 , 3 , 2 , 3 , 5 , 1 , 3 , 5 ,
      Nature Medicine
      Nature Publishing Group US
      Genetics research, Preventive medicine

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 ( P = 3.2 × 10 −9), which we replicated in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha variant waves compared to non-carriers (hazard ratio = 0.63, 0.42–0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (COVID-19) vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

          Abstract

          Variation in antibody levels elicited by the COVID-19 vaccine ChAdOx1 nCov-19 is linked to specific major histocompatibility complex class II alleles, providing insight into the breadth of immune response among vaccinated individuals.

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          Most cited references51

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          Highly accurate protein structure prediction with AlphaFold

          Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
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            Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

            Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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              PLINK: a tool set for whole-genome association and population-based linkage analyses.

              Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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                Author and article information

                Contributors
                alexander.mentzer@ndm.ox.ac.uk
                julian.knight@well.ox.ac.uk
                Journal
                Nat Med
                Nat Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                13 October 2022
                13 October 2022
                2023
                : 29
                : 1
                : 147-157
                Affiliations
                [1 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [2 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Oxford Vaccine Group, Department of Paediatrics, , University of Oxford, ; Oxford, UK
                [3 ]GRID grid.410556.3, ISNI 0000 0001 0440 1440, NIHR Oxford Biomedical Research Centre and Oxford University Hospitals NHS Foundation Trust, ; Oxford, UK
                [4 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, The Jenner Institute, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [5 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Chinese Academy of Medical Science (CAMS) Oxford Institute, , University of Oxford, ; Oxford, UK
                [6 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Division of Structural Biology, Wellcome Centre for Human Genetics, , University of Oxford, ; Oxford, UK
                [7 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Clinical Neurosciences, , University of Oxford, ; Oxford, UK
                [8 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Department of Biochemistry, , University of Oxford, ; Oxford, UK
                [9 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Population Health, , University of Oxford, ; Oxford, UK
                [10 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [11 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, , University of Oxford, ; Oxford, UK
                [12 ]GRID grid.410421.2, ISNI 0000 0004 0380 7336, School of Population Health Sciences, , University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, ; Bristol, UK
                [13 ]London Northwest University Healthcare, Harrow, UK
                [14 ]GRID grid.48004.38, ISNI 0000 0004 1936 9764, Department of Clinical Sciences, , Liverpool School of Tropical Medicine, ; Liverpool, UK
                [15 ]GRID grid.8756.c, ISNI 0000 0001 2193 314X, College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, , University of Glasgow, ; Glasgow, UK
                [16 ]GRID grid.420545.2, ISNI 0000 0004 0489 3985, Guy’s and St. Thomas’ NHS Foundation Trust, ; London, UK
                [17 ]GRID grid.415052.7, ISNI 0000 0004 0606 323X, MRC Clinical Trials Unit at UCL, ; London, UK
                [18 ]GRID grid.412563.7, ISNI 0000 0004 0376 6589, NIHR/Wellcome Trust Clinical Research Facility, , University Hospitals Birmingham NHS Foundation Trust, ; Birmingham, UK
                [19 ]GRID grid.420004.2, ISNI 0000 0004 0444 2244, Department of Infection and Tropical Medicine, , Newcastle upon Tyne Hospitals NHS Foundation Trust, ; Newcastle, UK
                [20 ]GRID grid.420004.2, ISNI 0000 0004 0444 2244, NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, ; Newcastle, UK
                [21 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Translational and Clinical Research Institute, Immunity and Inflammation Theme, , Newcastle University, ; Newcastle, UK
                [22 ]GRID grid.464526.7, ISNI 0000 0001 0581 7464, Public Health Wales, Cardiff, , Wales and Aneurin Bevan University Health Board, Wales, ; Cardiff, UK
                [23 ]GRID grid.240404.6, ISNI 0000 0001 0440 1889, School of Life Sciences, , University of Nottingham and Nottingham University Hospitals NHS Trust, ; Nottingham, UK
                [24 ]GRID grid.511123.5, ISNI 0000 0004 5988 7216, MRC - University of Glasgow Centre for Virus Research & Department of Infectious Diseases, Queen Elizabeth University Hospital, ; Glasgow, UK
                [25 ]GRID grid.500643.4, ISNI 0000 0004 7871 7239, NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, ; London, UK
                [26 ]GRID grid.5335.0, ISNI 0000000121885934, Department of Medicine, , Cambridge Heart Lung Research Institute, University of Cambridge, ; Cambridge, UK
                [27 ]GRID grid.9481.4, ISNI 0000 0004 0412 8669, Hull University Teaching Hospitals NHS Trust, ; Hull, UK
                [28 ]GRID grid.4464.2, ISNI 0000 0001 2161 2573, St. George’s Vaccine Institute, , University of London, ; London, UK
                [29 ]GRID grid.31410.37, ISNI 0000 0000 9422 8284, Department of Infection, , Sheffield Teaching Hospitals NHS Foundation Trust, ; Sheffield, UK
                [30 ]GRID grid.418484.5, ISNI 0000 0004 0380 7221, Severn Pathology, North Bristol NHS Trust, ; Bristol, UK
                [31 ]GRID grid.39489.3f, ISNI 0000 0001 0388 0742, Clinical Infection Research Group, Regional Infectious Diseases Unit, NHS Lothian, ; Edinburgh, UK
                [32 ]GRID grid.11835.3e, ISNI 0000 0004 1936 9262, Department of Infection, Immunity and Cardiovascular Diseases, , University of Sheffield, ; Sheffield, UK
                [33 ]GRID grid.430506.4, ISNI 0000 0004 0465 4079, NIHR Southampton Clinical Research Facility and Biomedical Research Centre, , University Hospital Southampton NHS Foundation Trust, ; Southampton, UK
                [34 ]GRID grid.5491.9, ISNI 0000 0004 1936 9297, Faculty of Medicine and Institute for Life Sciences, , University of Southampton, ; Southampton, UK
                [35 ]GRID grid.451056.3, ISNI 0000 0001 2116 3923, NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, ; London, UK
                Author information
                http://orcid.org/0000-0002-4502-2209
                http://orcid.org/0000-0002-6902-9886
                http://orcid.org/0000-0001-7802-7025
                http://orcid.org/0000-0002-7030-7839
                http://orcid.org/0000-0001-7855-0991
                http://orcid.org/0000-0001-6460-1372
                http://orcid.org/0000-0003-1055-0033
                http://orcid.org/0000-0003-4919-2632
                http://orcid.org/0000-0001-6324-6559
                http://orcid.org/0000-0001-7361-719X
                http://orcid.org/0000-0002-0377-5536
                Article
                2078
                10.1038/s41591-022-02078-6
                9873562
                36228659
                49e93cfc-7f54-4f0b-8b4e-c0356d8ad414
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 December 2021
                : 7 October 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000691, Academy of Medical Sciences;
                Award ID: SGL024\1096
                Award Recipient :
                Funded by: The ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy trials were funded by the UK National Institute for Health Research, UK Research and Innovation, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation, and the South African Medical Research Council.
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust (Wellcome);
                Award ID: 204969/Z/16/Z
                Award Recipient :
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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2023

                Medicine
                genetics research,preventive medicine
                Medicine
                genetics research, preventive medicine

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